Sahu Research Group

Principal Investigator: Abhiram Sahu, PhD

The major research emphasis of the laboratory is understanding the molecular and neurobiological basis of feeding, obesity, and diabetes, and the mechanisms of hypothalamic action of peripheral metabolic factors in controlling reproduction, particularly the mechanisms of leptin and insulin signaling in the hypothalamus.

Leptin, a product of the obese gene produced primarily in the fat cells, signals nutritional status to key regulatory centers in the hypothalamus, acting as a major signal regulating energy homeostasis by decreasing food intake and increasing energy expenditure. Paradoxically, in the majority of cases, human obesity is associated with hyperleptinemia and cannot be attributed to defects in leptin or its receptor, therefore suggesting a state of leptin-resistance in obese individuals. Thus, the focus of Dr. Sahu’s laboratory is understanding the role of leptin resistance in developing a new approach to prevent or treat obesity and associated disorders.

Before one can understand the mechanism of leptin resistance, it is essential to identify neural targets as well as the signal transduction mechanisms by which leptin action is mediated in the hypothalamus. To this end, the lab has identified several hypothalamic peptidergic systems as potential targets of leptin signaling, and PI3K-phosphodiesterase 3B-cAMP pathway, as a novel mechanism of leptin signaling in the hypothalamus. Since leptin resistance may be the major cause of obesity and obesity-related disorders in humans, the lab currently uses rat and mouse models of diet-induced obesity to address whether the connection between leptin resistance and obesity is due to an alteration in leptin receptor activity and/ or defects in leptin signal transduction mechanisms in specific neuronal systems.

The lab has recently demonstrated that the PI3K pathway of leptin signaling is impaired during the development of diet-induced obesity. Additionally, several brain-specific transgenic and knockout models are currently under development to address molecular mechanisms of central leptin resistance.

Research Projects

Leptin signaling in the hypothalamus and obesity:

One out of every two adult Americans is rated as medically obese, making obesity the number one health problem in the country. Since it is a major risk factor for heart disease, diabetes, stroke, hypertension, and morbidity, the treatment of obesity and associated disease entails enormous medical costs.

About a decade ago, leptin was identified as a key peripheral metabolic signal that regulates food intake, body weight, and reproduction. Because obese individuals have more leptin in their blood, it is hypothesized that leptin resistance may be the major cause of obesity in humans. Thus, research at the lab focuses on identifying the mechanisms of leptin resistance, particularly in the hypothalamic region of the brain, where body weight regulation is primarily mediated. In order to understand potential mechanisms of leptin resistance, it is critical to identify positive and negative mediators of leptin signaling.

Another focus of the lab’s research is studying the molecular mechanisms by which leptin acts in the hypothalamus. In this regard, several targets of leptin signaling in the hypothalamus have been identified. In addition, although leptin has been shown to act through the conventional JAK-STAT pathway of cytokine signaling, the lab has identified an alternative leptin-signaling pathway – PDE3B-cAMP pathway. Current research at the lab also focuses on the physiological role of the hypothalamic PDE3B–cAMP pathway in mediating leptin action in normal food intake and body weight regulation as well as its role during the development of central leptin resistance, obesity, and diabetes. 

Lab Members

Maitrayee Sahu, Lab manager

masahu@pitt.edu

Lab Alumni

Anantha S Metlakunta, PhD
Senior Scientific Officer
Virchow Biotech Pvt Ltd
Hyderabad, AP, India
 
Keiichi Koshinaka, PhD

Scientist, Division of Neurology, Respirology, Endocrinology, and Metabolism
Department of Internal Medicine
Faculty of Medicine
University of Miyazaki, Kiyotake
Miyazaki, Japan

Rekha Pal, PhD

Research Assistant Professor
Department of Surgery
Children’s Hospital of Pittsburgh of UPMC

Sandhya Gupta, PhD

Senior Scientist
Tissue Culture and Cryopreservation Unit
NBPGR, New Delhi

Selected Publications

  • Zhao AZ, Huan J-N, Gupta S, Pal R, & Sahu A. A Phosphatidylinositol 3-K - phosphodiesterase 3B - cyclic AMP pathway is involved in hypothalamic action of leptin on feeding. Nat Neurosci, 5:727-28, 2002.
  • Pal R & Sahu A. Leptin signaling in the hypothalamus during chronic central leptin infusion. Endocrinol, 144:3789-98, 2003.
  • Sahu, A. Mechanisms of leptin signaling in the hypothalamus: emphasis on energy homeostasis and leptin resistance. Frontiers in Neuroendocrinology, 24:225-53, 2003.
  • Sahu, A. Minireview: A hypothalamic role in energy balance with special emphasis on leptin. Endocrinol, 145: 2613-20, 2004.
  • Sahu A & Metlakunta AR. Hypothalamic Phosphatidylinositol 3-kinase-Phosphodiesterase 3B-cyclic AMP pathway of leptin signaling in the hypothalamus is impaired following chronic central leptin infusion. J Neuroendocrinol, 17:720-26, 2005.
  • Sahu, A. Alteration in hypothalamic neuropeptide Y (NPY) secretion may underlie the female reproductive aging: induction of steroid-induced luteinizing hormone surge by NPY in ovariectomized old rats. J Neuroendocrinol, 18:584-93, 2006.
  • Metlakunta AR, Sahu M, & Sahu A. Hypothalamic Phosphatidylinositol 3-kinase pathway of leptin signaling is impaired during the development of diet-induced obesity in FVB/N mice. Endocrinol, 149:1121-28 (doi: 10.1210/en.2007-1307), 2008.
  • Sahu, A. Effects of chronic central leptin infusion on proopiomelanocortin and neurotensin gene expression in the rat hypothalamus. Neurosci Lett, 440:125-129 (doi:10.1016/j.neulet.2008.05.083). 2008.

Publications on PubMed

View Publications on PubMed